Cardiac Optogenetics in Atrial Fibrillation: Current Challenges and Future Opportunities

Abstract

Although rarely life-threatening on short term, atrial fibrillation leads to increased mortality and decreased quality of life through its complications, including heart failure and stroke. Recent studies highlight the benefits of maintaining sinus rhythm. However, pharmacological long-term rhythm control strategies may be shadowed by associated proarrhythmic effects. At the same time, electrical cardioversion is limited to hospitals, while catheter ablation therapy, although effective, is invasive and is dedicated to specific patients, usually with low amounts of atrial fibrosis (preferably Utah I-II). Cardiac optogenetics allows influencing the heart’s electrical activity by applying specific wavelength light pulses to previously engineered cardiomyocytes into expressing microbial derived light-sensitive proteins called opsins. The resulting ion influx may give rise to either hyperpolarizing or depolarizing currents, thus offering a therapeutic potential in cardiac electrophysiology, including pacing, resynchronization, and arrhythmia termination. Optogenetic atrial fibrillation cardioversion might be achieved by inducing a conduction block or filling of the excitable gap. The authors agree that transmural opsin expression and appropriate illumination with an exposure time longer than the arrhythmia cycle length are necessary to achieve successful arrhythmia termination. However, the efficiency and safety of biological cardioversion in humans remain to be seen, as well as side effects such as immune reactions and loss of opsin expression. The possibility of delivering pain-free shocks with out-of-hospital biological cardioversion is tempting; however, there are several issues that need to be addressed first: applicability and safety in humans, long-term behaviour, anticoagulation requirements, and fibrosis interactions.

Novel Pulmonary Delivery of Drugs for the Management of Atrial Fibrillation

“…The marketed NOACs include apixaban, dabigatran, edoxaban and rivaroxaban, which are available in a range of doses for a range of indications. However, the use of these anticoagulants with currently available dosage forms is associated with limited effectiveness and an increased risk of dose-related major bleeding [ 1 , 2 , 6 ]. Warfarin is recommended in clinical guidelines for the management of valvular AF and NVAF although long-term use requires frequent blood tests and involves the difficulty of achieving stable international normalized ratios, making therapy complex for physicians and patients.…”

“…Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia worldwide and is associated with increased mortality and decreased quality of life through its complications such as heart failure and stroke [ 1 , 2 ]. It has been reported that more than 335 million people are suffering from AF globally [ 3 ].…”

Optical modulation of excitation-contraction coupling in human-induced pluripotent stem cell-derived cardiomyocytes

“…Optogenetics, 4 , 5 , 6 , 7 , 8 , 9 that has become widespread in neuroscience, could in principle be relevant in the cardiac field too. 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 However, the approach still has a limited clinical applicability mainly because cell optical sensitivity is obtained by transduction with gene constructs carried by viral vectors.…”

Ultra‐low power deep sustained optogenetic excitation of human ventricular cardiomyocytes with red‐shifted opsins: a computational study

“…Cardiac optogenetics has the potential to overcome limitations associated with electrical stimulation of heart that include high‐voltage shocks, low‐specificity, non‐synchronous depolarization, and myocardial tissue damage, and thus it may become established as an alternative method for electrical control of the heart (Entcheva & Kay, 2020; Williams & Entcheva, 2015). It offers a therapeutic potential in cardiac electrophysiology that includes restoration of pacemaking ability, cardiac resynchronization, mimicking and terminating cardiac arrhythmias, suppression and manipulation of rotors in cardiomyocyte monolayers, and elucidation of the function of both cardiomyocyte and non‐cardiomyocyte cellular subpopulations in the heart (Bruegmann et al., 2016; Floria et al., 2020; Nyns et al., 2017; O'shea et al., 2019; Wang et al., 2017).…”